Immunoisolation and transplantation of primary or genetically engineered cells of allo- or xenogenic origin holds great potential to treat many hormone and enzyme deficiency disorders. The principle application of the technology has been the treatment of a wide variety of endocrine disease, including diabetes mellitus, hypoparathyroidism, dwarfism, central nervous system diseases, including Parkinson's, Alzheimer's, ALS, other genetic disorders including lysosomal storage disorders (LSDs), hemophilia as well as other conditions like kidney and/or liver failure and cancer.
The basic idea of microencapsulation is to entrap cells in a semi-permeable polymeric hydrogel and implant them into the body where, ideally, they remain undetected by the immune system for as long as possible. Often, the hydrogel alone is too permeable, so it is coated with a thin permeability-controlling shell. The most common type of microcapsule is the alginate-poly-L-lysine (PLL)-alginate (APA) capsule. An APA capsule consists of a calcium-alginate hydrogel core, surrounded by PLL (a polycation) and a final coating of alginate (a polyanion). The major advantages to using alginate are that it is processable at physiological conditions, and it does not interfere with cellular function.
However, the inconsistencies associated with alginate (a naturally occurring polysaccharide, composed of varying amounts of β-D-manuronic (M) and α-L-guluronic (G) acids, when isolated from different sources and purified by different procedures, is a major disadvantage. In terms of an immune response, alginate has been shown to contain variable amounts of inflammatory or immunogenic proteins, polyphenols and endotoxins. These compounds may cause fibrotic overgrowth around the capsule, leading to cell asphyxiation. In terms of mechanical strength, capsule failure after transplantation has been attributed to weakening of the calcium-alginate core caused by exchange of calcium for sodium in the body, followed by core swelling and rupture of the immuno-isolating outer shell. As well, alginate has recently been reported to degrade by oxidative-reductive and hydrolytic processes in the body, raising further concerns about long-term applications. At best, alginate varies with harvest location and harvesting methods, and requires substantial purification to be acceptable for human use.
To improve APA capsules, synthetic polymers have been utilized with varying degrees of success. The use of synthetic polymers permits manipulation to alter polymeric properties and avoids residual biological impurities found in naturally occurring polymers. A diversity of covalent modifications utilizing synthetic polymers have been used to improve the mechanical and chemical stability, permeability, and biocompatibility of APA microcapsules. In this regard, polymer-bound reactive groups have been utilized which are typically less toxic, for example, covalent cross-links throughout a linear pluronic polymer (a triblock copolymer of poly(ethylene glycol) and poly(propylene glycol)) hydrogel core, using Michael-type addition between pluronic chains having thiol and acrylate end groups have been used, as well as microcapsules that form covalent bonds through photodimerization of modified poly(allylamine) or PLL in the capsular membrane. The use of a reactive polyanion-bearing acetoacetate groups that form covalent crosslinks with poly-L-lysine has also been described.
However, there remains a need to provide an improved hydrogel system which overcomes or at least reduces the disadvantages of existing systems, for example, immunological incompatibility, including for example, undesirable binding to endogenous proteins. In particular, existing crosslinking systems tend to contain residual functional groups even after crosslinking, and these may subsequently bind proteins or undergo other undesirable reactions.